Published Ahead of Print on December 13, 2013, as doi:10.3324/haematol.2012.083097. Copyright 2013 Ferrata Storti Foundation. Combination therapy of hydroxycarbamide with anagrelide in patients with essential thrombocythemia in the evaluation of Xagrid® efficacy and long-term safety study by Luigi Gugliotta, Carlos Besses, Martin Griesshammer, Claire Harrison, Jean-Jacques Kiladjian, Ruth Coll, Jonathan Smith, Brihad Abhyankar, and Gunnar Birgegård Haematologica 2013 [Epub ahead of print] Citation: Gugliotta L, Besses C, Griesshammer M, Harrison C, Kiladjian JJ, Coll R, Smith J, Abhyankar B, and Birgegård G. Combination therapy of hydroxycarbamide with anagrelide in patients with essential thrombocythemia in the evaluation of Xagrid® efficacy and long-term safety study. Haematologica. 2013; 98:xxx doi:10.3324/haematol.2012.083097 Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process. Combination therapy of hydroxycarbamide with anagrelide in patients with essential thrombocythemia in the evaluation of ® Xagrid efficacy and long-term safety study Luigi Gugliotta,1 Carlos Besses,2 Martin Griesshammer,3 Claire Harrison,4 Jean-Jacques Kiladjian,5 Ruth Coll,6 Jonathan Smith,6 Brihad Abhyankar,7 and Gunnar Birgegård8 1Department of Hematology “L. e A. Seragnoli”, St Orsola-Malpighi Hospital, Bologna, Italy 2Department of Hematology, Hospital del Mar-IMIM, Barcelona, Spain 3Hematology and Oncology, Johannes Wesling Klinikum Minden, Minden, Germany 4Department of Hematology, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom 5AP-HP, Hôpital Saint-Louis, Centre d’Investigations Cliniques, Paris, France 6Shire Pharmaceuticals Ltd, Basingstoke, United Kingdom 7Former employee of Shire Pharmaceuticals Ltd, Basingstoke, United Kingdom, and 8Department of Hematology, Uppsala University, Uppsala, Sweden Running head: Hydroxycarbamide + anagrelide in the EXELS study Correspondence: Luigi Gugliotta, Department of Hematology, “L. e A. Seragnoli”, St Orsola-Malpighi Hospital, 40138 Bologna, Italy. E-mail: [email protected]. Trial registration: clinicaltrials.gov identifier: NCT00567502; Protocol No.: SPD422-401 1 Acknowledgments The study was designed by the international EXELS steering committee (J-J Kiladjian, C Besses, M Griesshammer, L Gugliotta, C Harrison), chaired by G Birgegård. Under the direction of the authors, Kerry Acheson and Sasha Mitchell, employees of iMed Comms, provided writing assistance for this publication. Editorial assistance in formatting, proofreading, copy editing, and fact checking was also provided by iMed Comms. iMed Comms was funded by Shire for support in writing and editing this manuscript. Although the sponsor was involved in the design, analysis, interpretation, and fact checking of information, the content of this manuscript, the ultimate interpretation, and the decision to submit it for publication in Haematologica was made by the authors independently. The authors acknowledge the contribution of all investigators who participated in this study (Appendix). Funding The study was supported by Shire Development LLC, the sponsor, and was agreed with the European agency as a Post Approval Commitment and overseen by the international EXELS steering committee (J-J Kiladjian, C Besses, M Griesshammer, L Gugliotta, C Harrison), chaired by G Birgegård. Editorial assistance in writing, formatting, proofreading, copy editing, and fact checking was provided by iMed Comms and funded by Shire. 2 Abstract Limited information is available regarding the use of cytoreductive combination therapy in high-risk patients with essential thrombocythemia. This analysis aims to evaluate the clinical relevance and patterns of cytoreductive combination treatment in European high-risk patients with essential thrombocythemia in the Evaluation of Xagrid® Efficacy and Long-term Safety study. From 3643 patients, 347 (9.5%) received combination therapy. Data were recorded at each 6-month update. Of 347 patients who received combination therapy, 304 (87.6%) received hydroxycarbamide + anagrelide. Monotherapies received before this combination were hydroxycarbamide (n=167; 54.9%) and anagrelide (n=123; 40.5%). Median weekly doses of hydroxycarbamide and anagrelide were: 7000 and 10.5 mg when used as prior monotherapy; 3500 and 7.0 mg when used as add-on treatment. Overall, median platelet counts were 581x109/L and 411x109/L before and after starting hydroxycarbamide + anagrelide, respectively. In patients with paired data (n=153), the number of patients with platelet counts < 400x109/L increased from 33 (21.6%) to 74 (48.4%, P<0.0001), and with platelet counts < 600x109/L, from 82 (53.6%) to 132 (86.3%, P<0.0001). Hydroxycarbamide + anagrelide was discontinued in 158 patients: 76 (48.1%) stopped hydroxycarbamide, 59 (37.3%) stopped anagrelide, 19 (12.0%) stopped both and 4 (2.5%) had another therapy added. The most frequent reasons for discontinuation were intolerance/side effects, lack of efficacy, and therapeutic strategy. Combination therapy, usually hydroxycarbamide + anagrelide, is used in approximately 10% of all high-risk patients with essential thrombocythemia and may be a useful approach in treating patients for whom monotherapy is unsatisfactory. This trial is registered on clinicaltrials.gov (NCT00567502). Key words: Essential thrombocythemia, anagrelide, hydroxycarbamide, combination therapy, EXELS study. 3 Introduction Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by proliferation of megakaryocytes and an increased risk of developing thrombohemorrhagic complications.1 Current therapy for ET is not curative, and is therefore guided by the need to minimize the incidence of thrombohemorrhagic events, to control disease-related symptoms, and to reduce primary and iatrogenic disease progression, where possible.2-4 The primary goal of cytoreductive therapy, recommended for patients with ET categorized as high-risk (> 60 years, or platelet count > 1500x109/L, or a history of thrombohemorrhagic events2), is to attain a complete clinicohematologic response (platelet count ≤ 400x109/L, no disease-related symptoms, normal spleen size, white blood cell [WBC] count < 10x109/L).2-6 According to European LeukemiaNet (ELN) guidelines, hydroxycarbamide (HC) is currently recommended as first-line therapy in high-risk patients with ET, although its use should be carefully considered in younger patients (< 40 years old).2 Anagrelide is indicated as second-line therapy in Europe for high-risk patients with ET who are intolerant to their current first-line therapy.7 Other second-line therapies for management of ET include busulfan (licensed indication), interferon-α (IFN; unlicensed indication), and pipobroman (unlicensed indication).5 Long-term treatment with cytoreductive agents can be accompanied by side effects often leading to dose reductions, which may in turn lead to reduced efficacy. As a means to overcome inadequate efficacy, or to avoid dose-limiting toxicities with monotherapy, combination therapy of two cytoreductive drugs, usually HC plus anagrelide, has been reported by the Anagrelide Study Group in around one-fifth of treated patients with ET.8,9 Moreover, a combination of anagrelide with either HC or IFN has been mentioned as a practical option for treatment of selected patients with ET10-12 and recent clinical data are now available.13-16 There are currently no guidelines in place to guide the use of combination therapy in ET, thus the decision to undertake this treatment is at the discretion of the treating physician. Evaluation of Xagrid® Efficacy and Long-term Safety (EXELS) is a post-approval commitment observational study designed to monitor the safety and pregnancy outcomes of anagrelide and other cytoreductive therapies in a large European cohort of patients with ET. In the EXELS study, a cohort of patients was identified as being treated with anagrelide in combination with another cytoreductive drug. The aim of this subanalysis is to describe the use of combination therapy in patients with ET, with a focus on HC + anagrelide, and to discuss its role in clinical practice. 4 Methods Trial design EXELS is an ongoing phase IV, observational, multicenter, safety study in high-risk patients with ET being treated with cytoreductive therapy (NCT00567502). The primary objective of the EXELS study is to monitor safety and pregnancy outcomes of anagrelide and other cytoreductive therapies in high-risk patients with ET. Secondary objectives include assessment of efficacy (platelet reduction and incidence of thrombohemorrhagic events) and drug utilization (drug type, drug dose, and duration of exposure). The study is being conducted in 13 European countries: Denmark, Finland, France, Germany, Greece, Ireland, Italy, Netherlands, Norway, Portugal, Spain, Sweden, and the United Kingdom. All participating centers obtained ethical